selection of and updating avian influenza vaccine seed ... · vaccine/vaccination terminology •...
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Selection of and Updating
Avian Influenza Vaccine Seed
Strains to Maintain Vaccine
Efficacy in the Face of Field
Virus Drift
David E. Swayne
OIE Collaborating Centre for Research On
Emerging Avian Diseases, FAO Reference Centre
for Avian Influenza, and Exotic & Emerging
Avian Viral Diseases Research Unit
SEPRL, ARS, USDA, Athens, Georgia, USA
Vaccine/Vaccination Terminology
• Efficacy: vaccine passes a lab challenge test
• Effectiveness: vaccine provides protection under field
conditions (implies proper application & coverage)
• Potency: adequate amount of antigen (HA) to
provide a strong immune response in field
– Direct (Ag [HA] content, e.g. 0.3-7.8 μg or 512 HA
units/dose) or indirect assessment (HI titers in immunized
poultry, e.g. ≥ 1:32)
– Determine mean protective dose (PD50); e.g. minimal 50
PD50 per dose (50 PD50)
• Surveillance: looking for H5 virus in field
• Monitoring: looking at vaccinated flocks for
serotiters indicating protection and coverage
Historically - Broad cross protection within a
hemagglutinin subtype; i.e. H5N2, H5N9, etc.
protects against H5N1 HPAI viruses (inactivated
AI and live recombinant vaccines)
Experimental protection studies support the claim
Field success in using existing H5 vaccines in H5N1
HPAI control in Asia: e.g. Mexican, USA and
European H5 vaccine strains in Asia
Introduction
• Historical H5 Vaccines –
Similar antigenicity: wild birds
viruses and initial AI outbreak
viruses in poultry (Swayne et al., Av Dis
45:355-365, 2001)
• As the virus lineage becomes
enzootic in gallinaceous
poultry, the HA drifts away
from root
(A/ck/WIJ-PWT/06)
(A/ck/SMI-HAMD/06)
HA Subtype Cross Protection
Antigenic Cartography
(Updated from Swayne et al., Vaccine 18:1088-1095. 2000)
* challenge viruses
Homosubtypic HA Protection by AI Vaccines
• Fowl pox with H5
AIV gene insert
• Different challenge
viruses (87.3-100% aa
sequence similarity)
TK/Ireland/1378/83
Dk/Ireland/113/83
CK/Scotland/59
Tern/South Africa/61
Peking Duck/Malaysia/645/97
TK/England/50-92/91
CK/Hong Kong/220/97
Hong Kong/156/97
Whooper Swan/Mongolia/244/2005
CK/Korea/ES/03
CK/Vietnam/2004
CK/Italy/1485/97
CK/PA/13609/93
Emu/Tx/39442/93
Tk/Ontario/7732/66
CK/PA/1370/83
TK/WI/68
Dk/Michigan/80
Ruddyturnstone/NJ/2242/00
Ck/Queretaro/7653-20/95 5 changes
N. Amer.
Eurasian * *
*
* *
*
* *
*
*
*
Chickens vaccinated SQ 1d with rFP-H5-Ire/83 and IN challenged at 3
wks with 105-6 EID50 of HPAIV
Decreasing AIV Susceptibility:
Biotechnology to Solve Genetic Drift
Ck/Scotland/59 H5N1 92 0/10
Tern/S. Afr/61 H5N3 93.1 0/10
Tk/Ontario/66 H5N9 89.1 0/10
Ck/PA/83 H5N2 87.3 0/10
Tk/Ireland/83 H5N8 100 0/10
Tk/England/91 H5N1 94.2 0/10
Ck/Queretaro/95 H5N2 89.3 0/10
HK/156/97 H5N1 90.2 0/10
Ck/S. Korea/03 H5N1 89.9 0/10
ck/Vietnam/04 H5N1 88.4 est 0/22
WS/Mongolia/05 H5N1 89.7 1/8
Control - - 80-100%
SubtypeChallenge Virus
HA
Similarity
to Tk/Ire/83
Mortality
(MDT)
• Excellent protection
from mortality using
diverse H5 AIV
• Reduction in virus
replication and
shedding from
respiratory and
digestive tracts
(Swayne et al., Vaccine 18:1088-1095. 2000)
• Higher HA identify between vax and challenge AIV
• Respiratory shedding – significant reduction
• Alimentary shedding – no association in reduction
(Swayne et al., Vaccine 18:1088-1095. 2000)
Oropharangeal Swabs - Peak Shedding
1 1.5 2 2.5 3 3.5 4 4.5
Cloacal Swabs - Peak Shedding
1 1.5 2 2.5 3 3.5 4 4.5
rs = 0.783, P = 0.009 rs = -0.100, P = 0.780
Reduction in Titer (Log 10)
% H
ema
gglu
tin
in I
den
tity
Homosubtypic HA Protection by AI Vaccines
rFP-H5 vaccines, pre-2005 challenge HPAI viruses
• H5 viruses are diverse – N.
Amer. and Eurasian lineages
• H5N1 HPAI is not a single
virus, but a family of viruses
with 10 lineages and many
sublineages
• Virus is drifting as other
influenza A viruses have
done –from natural
infections and “vaccine
pressure”
Changing Genetic
Diversity
WHO WHO
Antigenic Diversity of H5N1 Avian
Influenza Virus: AgC-H5 (Ferret Serum)
Source: Ron Fouchier
Antigenic Diversity of H5N1 Avian Influenza
Virus: AgC-H5 (Chicken Serum)
Source: Erica Spackman
• Historical H5 Vaccines –
Similar antigenicity
• Drifting of HA away from
root
• Good protection:
Ck/HK/220/97, Ck/Legok/03,
VN/1203/04, Ck/WJ/HAMD/06
• Intermediate protection:
Ck/Papua/06
• Poor protection: PWT/06 (A/ck/WIJ-PWT/06)
(A/ck/SMI-HAMD/06)
G
I
P
Impact of Drift on Protection
Antigenic Cartography
Other Examples of Antigenic Drift
• Egypt (2006-): Field HPAIV resistance to immunity from
Mexico/94 and Re-1 vaccines (Cattoli et al, J.Virol. 85:8718-8724, 2011
and Grund et al., Vaccine 29:5567-5573, 2011)
• China (2004-) (Chen et al., OIE Rev Sci Tech 28:267-274, 2009):
– Tk/England/1973 [H5N2]: (2004-6)
– Re-1 (rg A/gs/Guangdong/1/1996 [H5N1] (0): 2004-8
– Re-4 (rgA/ck/Shanxi/2006 [H5N1](7): 2006-7
– Re-5 (rgA/dk/Anhui/1/2006 [H5N1](2.3.4): 2008-12
– Re-6 (rgA/dk/Guangdong/S1322/2010 [H5N1] (2.3.2): 2012-
• Vietnam: 2011 2.3.2.1B resistant to immunity from Re-1 &
Re-5 (now use Re-6) (Cha et al. Vaccine 31:4953-4960, 2013)
• Hong Kong (2008): clade 2.3.4 on 1 farm (Leung et al., Vaccine
31:3536-3542, 2013)
– Mexico (LPAI): North American H5N2 (Lee et al.,
J.Virol. 78:8372-8381, 2004; Eggert et al., Vaccine 28:4609-4615,
2010 )
Antigenic drift must be continually addressed &
vaccine seed strains updated; future will require
reverse genetic LPAI seed strains based on
hemagglutinin of recent field HPAIV
How do you update?
Ongoing and adequate surveillance and monitoring in
vaccinated and non-vaccinated populations
• Passive surveillance for mortality events in all vaccinated
flocks and subset of non-vaccinated flocks – VI and
sequencing of isolates
• Active surveillance in subset of vaccinated flocks with normal
mortality profile – VI on deads as routine with sequencing of
isolates
• Ongoing genetic analysis of all H5 viruses (phylogeny)
• Subset of genetically diverse isolates are HI tested &
analyzed for antigenic divergence (cartography)
• Challenge testing of subset of antigenic divergent viruses
• Proposed seed strain change based on frequency of
antigenic variant viruses in field
What Does This Mean?
Global marketing of a single H5 vaccine seed strain does not
always meet the local (national/regional) needs for efficacy;
i.e. science and not marketing should prevail
Solutions:
• Best: Updating vaccine seed strains to match antigenic drift in
field viruses (reverse genetic seeds to match field virus)
• Adjunct: Increase antigen mass in inactivated vaccine – HA
protein quantity (HA units or 50 PD50) (Source: CLEVB Egypt, challenge
tests for vaccine batch release)
• Adjunct: Multiple vaccinations to enhance immunity in field – use
of heterologous H5 vaccine seeds (bivalent or multiple
heterogenous monovalent)
o Prime-Boost usage
o More use of live recombinants in hatchery
• Adjunct: Adjuvants to enhance immune response (current
[proprietary] & future [oils, surfactants & cytokines])
Increasing Antigen Content
Current National Minimum Standard: 1:40 (1:32)
hemagglutination inhibition (HI) titer (SPF WL lab
conditions): Mortality protection
• HI serology titers of GMT ≥ 8 (Swayne et al., Av Pathol 28:245-255, 1999) or
≥10 (Kumar et al., Av Dis 51:481-483, 2007) were associated with survival
when had antigenically similar seed and challenge viruses
• HI serology titers of GMT ≥ 40 (Kumar et al., Av Dis 51:481-483, 2007) were
associated with prevention of challenge virus shedding from the
oropharynx in the majority of vaccinated chickens and GMT ≥ 128
(Swayne, et al., Av Path 35:141-146, 2006) were associated with preventing
challenge virus shedding from the oropharynx in all vaccinated
chickens
• Newer Data: HI serology titers (challenge virus antigen) of GMT ≥
32 associated with survival and GMT ≥ 64 associated with
preventing respiratory replication
Increasing Antigen Content
Proposed National Minimum Standard: GMT ≥ 120
(128) HI titer as optimal (using vaccine seed as HI
test antigen)
If HI test using challenge or antigenic drift variants
produce mean titers of GMT ≤ 32, vaccine seed
change should be further examined
– Challenge studies to assess protection
– Examine other field viruses in HI tests to determine how
common the antigenic variant viruses are in the field
Other Related Issues
Pre-develop logistics for vaccination and exercise
vaccination plan for emergency or ‘routine’ usage
Vaccine availability: commercially or vaccine bank within
the country
• Completed vaccine licensing/registration process, or have
emergency authority
• Stockpiles available in country through manufacturing capacity
or importation to meet need
License issues:
• Specific seed strain for each license submission
• Replacing seed strain requires additional data and varies with
each country: safety to full efficacy and potency
• Cassette concept – seed strain replacement with safety
and seropotency data
Conclusions
• Genetic and antigenic variant HPAI/LPAI field viruses,
resistant to licensed H5 AI vaccines, have been
identified in Mexico, Indonesia, Egypt, Vietnam, Hong
Kong and China
• Updating vaccine seed strains is needed to assure the
most efficacious and effective vaccines are used in the
field
• More rg inactivated seed strains and recombinant
vaccines will be needed for antigenic matching
• Need more rapid means of licensing updates in vaccine
seed strains through national regulatory processes
Conclusions
• Increasing antigen content in vaccines, using multi-
vaccinations with antigenically diverse seeds, or single
vaccination with bivalent vaccines (with antigenically
diverse seeds) can compensate for some antigenic
diversity of field viruses, but will not replace the
periodic need to update seed strains
• Need to update the minimum potency of all H5 and H7
AI vaccines
Merci Beaucoup!
Thanks: OIE: K. Hamilton, G.
Pavade. B. Vallat,
FAO: G. Dauphine, J.
McGrane, J Lubroth, M.
Kim
SEPRL: D. Suarez, E.
Spackman, Mary Jackwood,
D. Kapczynski
Others: T. Prajitno, D.
Smith, R. Fouchier